Chronic Urticaria and Autoimmunity

Kathleen Fraser BHSc¹ and Lynne Robertson MD, FRCPC²

¹College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
²Section of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

ABSTRACT
Chronic urticaria is defined as hives, typically occurring daily, for greater than 6 weeks duration. Chronic idiopathic urticaria, which has no discernable external cause, comprises the majority of cases of chronic urticaria. Over half of all cases of chronic idiopathic urticaria are thought to occur by an autoimmune mechanism, primarily autoantibodies against the high affinity immunoglobulin E (IgE) receptor (FcεRI). Chronic urticaria is hypothesized to occur because of a predilection in the patient to develop reactions to self. Supporting this hypothesis, a strong association has been found between chronic urticaria and additional autoimmune diseases, such as thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, celiac disease and type 1 diabetes, among others. Herein, we review the associations between chronic urticaria, thyroid disease, and other autoimmune disorders, as well as the implications that these correlations hold for therapeutic intervention in chronic urticaria.

Key Words:
angioedema, antibodies, autoimmune disease, chronic disease, comorbidities, complications, hives, hypersensitivity, inflammation, thyroid disease, urticaria

Introduction

It is estimated that urticaria will affect 25% of the population at some point in their lifetime.¹ Chronic urticaria (CU) involves hives, typically occurring daily, for greater than 6 weeks duration. CU generally lasts 1 to 5 years, but can have a prolonged course beyond 5 years in roughly 14% of patients.² Individuals affected by CU have reported emotional distress, feelings of isolation and fatigue in response to their condition, similar to findings in patients with ischemic heart disease.³ This underscores the importance of managing CU appropriately to minimize both physical and psychological impacts of this disease.

CU can occur in response to drugs, physical stimuli, as part of inflammatory or inherited diseases, or can be idiopathic in nature. Acetylsalicylic acid (ASA) or nonsteroidal anti-inflammatory drug (NSAID) intolerant CU is hypothesized to occur due to inhibition of the cyclooxygenase pathway, which causes enhanced production of leukotrienes.⁴ The physical urticarias (classically divided into heat, cold, solar, vibration, delayed-pressure, dermatographism, aquagenic and cholinergic induced urticaria) occur in response to external stimuli.⁵ Urticarial vasculitis involves the appearance of urticarial lesions lasting greater than 24 hours in the hisopathological setting of vasculitis.⁶ Inherited syndromes with CU include the spectrum of cryopyrinopathies, such as Familial Cold Autoinflammatory syndrome, Muckle- Wells syndrome, and Neonatal-Onset Multisystem Inflammatory Disease/Chronic Infantile Neurologic Cutaneous Articular syndrome (NOMID/CINCA).⁷ Urticaria presents as a feature of many inflammatory disorders, such Schnitzler syndrome,⁸ Still’s disease,⁹ and Gleich’s syndrome¹⁰. Chronic idiopathic urticaria, unlike the physical urticarias and ASA or NSAID intolerant variants, has no discernable external cause.¹¹

Chronic idiopathic urticaria is the most common type of CU, comprising up to 90% of all cases of CU.¹ It has been estimated that chronic idiopathic urticaria will affect between 0.6%¹² to 5%¹³ of the population during their lifetime. Over half of all cases of chronic idiopathic urticaria are thought to be caused by an autoimmune mechanism.¹⁴ This is supported by the observation that 60% of patients with chronic idiopathic urticaria will have a wheal and flare reaction to intradermal autologous serum injections in the autologous serum skin test (ASST).¹⁵ Approximately 50% of patients with chronic idiopathic urticaria have IgG antibodies that are specific for the high affinity IgE receptor (FcεRI).^14,16 These autoantibodies activate mast cells in the skin, circulating basophils, and the complement system.¹⁴ Additional immunological abnormalities described to play a causative role in CU include IgG antibodies directed against IgE antibodies and the low affinity IgE receptor (FcεRII),¹⁷ antiendothelial antibodies,¹⁸ and complement C8 alpha-gamma (C8α-γ) deficiency¹⁹.

In patients with chronic idiopathic urticaria, approximately 35% will experience episodes of angioedema and 25% are positive for dermatographism.²⁰ Like many autoimmune diseases, chronic idiopathic urticaria has a higher incidence in women than men, with the reported ratio of females to males ranging from 2:1^21,22 to 4:1²³. Numerous autoimmune conditions have been associated with chronic idiopathic urticaria, including thyroid disease, celiac disease, and rheumatoid arthritis (RA).

The purpose of this review is to discuss the association of CU with thyroid disease and other autoimmune diseases, as well as the implications that these associations hold for therapeutic intervention in CU.

Thyroid Disease and Chronic Urticaria

Thyroid disease is the most commonly reported autoimmune condition in patients with CU. In the literature, the frequency of thyroid autoimmunity in patients with CU encompasses a vast range of values, varying from 6.5%²⁴ to 57%²⁵. Patients with coexistent thyroid autoimmunity and CU have a more severe and prolonged course of urticaria than those without thyroid autoimmunity.²⁶

In patients affected by both CU and thyroid autoimmunity, there is an increased risk of developing angioedema. Leznoff and Sussman reported that the triad of thyroid autoimmunity, CU, and angioedema occurred in 15% of patients with CU.²⁷ The risk of developing angioedema in patients with thyroid autoimmunity and CU is estimated to be 16.2 times greater than those with CU without thyroid autoimmunity.²⁸

In a recent large study of 12,778 CU patients by Cofino-Cohen et al., it was found that 9.8% of patients had hypothyroidism, compared with 0.6% in the control group.²¹ Hypothyroidism was the most commonly detected thyroid disease in patients with CU. Females were more likely to be affected by the combination of hypothyroidism and CU than their male counterparts. Patients with hyperthyroidism and CU comprised 2.7% of the study population, compared to 0.09% in the control group. In most patients, the thyroid disease was identified in the 10 years following the diagnosis of CU. This implies that thyroid autoimmunity developed subsequent to the initial presentation of CU. In the same study, anti-thyroid antibodies were significantly more common in CU patients than controls. Of the patients with CU who were clinically euthyroid, anti-thyroperoxidase antibodies were found in approximately 2.7% and antithyroglobulin antibodies were found in 0.6%. Aamir et al. also noted the association between anti-thyroid antibodies and CU, as anti-thyroglobulin and anti-microsomal antibody levels were significantly increased in patients with CU and hypothyroidism.²⁵

The development of thyroid disease is often considered to be a marker of autoimmunity. Thyroid disease has been connected to a variety of autoimmune diseases, including pernicious anemia, celiac disease, type 1 diabetes and systemic lupus erythematosus (SLE), in addition to CU.²⁹ Although a specific mechanism linking the development of thyroid disease and CU has yet to be firmly elucidated, it is widely thought that both diseases occur because of a propensity within the patient to develop reactions to self. It has been hypothesized that thyroid disease may worsen urticaria and angioedema through activation of the complement system. Blanchin et al. demonstrated the thyroperoxidase enzyme contains a domain that binds to complement protein C4, cleaving it to C4a and activating the classical pathway of the complement cascade.³⁰ Kirpatrick noted that C4a levels decrease when thyroid disease is treated, resulting in remission of CU.³¹ Therefore, while it is hypothesized that thyroid disease and CU may coexist due to a patient’s predilection for autoimmunity, thyroid disease may additionally exacerbate urticaria and angioedema through direct mechanisms that result in complement activation.

Other Autoimmune Diseases and Chronic Urticaria

Beyond thyroid disease, a variety of additional autoimmune diseases have been examined for associations with CU. Confino- Cohen et al. found that 12.5% of patients had one additional autoimmune disease, 2.1% had two diseases, 0.1% had three diseases, and single patients each had an additional four or five diseases. Of patients with CU and hypothyroidism, RA was the most frequently identified additional autoimmune disease. The odds of having RA were 13.25 times higher in those with CU than in the control group.²¹ The major laboratory marker of RA, rheumatoid factor, was reported by Ryhal et al. to be significantly increased in patients with CU.³²

The risk of developing type 1 diabetes is increased in CU patients of both genders. In women with CU, the development of Sjögren’s syndrome, celiac disease, or SLE was significantly higher than controls. Most patients received their diagnosis of an additional autoimmune disease in the 10 years following the CU diagnosis,²¹ which emphasizes that these diseases developed subsequently and were not incidentally picked up at the time of CU diagnosis. The association of celiac disease and CU has previously been highlighted in the pediatric population.^33,34 Raynaud’s phenomenon with positive anti-centromere antibodies was described with CU by Asero et al.³⁵ Additional autoimmune diseases such as vitiligo and pernicious anemia have also been associated with CU.³⁶

CU has been shown to have a genetic association to the human leukocyte antigen (HLA)-DR4 and HLA-DQ8 alleles.³⁷ Interestingly, HLA-DR4 is strongly associated with RA,³⁸ and HLADQ8holds associations with celiac disease³⁹ and type 1 diabetes⁴⁰. Complement deficiencies have been associated with autoimmune diseases, such as Sjögren’s syndrome,⁴¹ RA,⁴² and SLE,⁴³ and Park et al. have reported the development of CU, anti-nuclear antibodies and spondyloarthropathy in a 9 year old boy with C8α-γ deficiency¹⁹. CU was described in a 10 year old boy with a strong autoimmune phenotype.⁴⁴ The full inventory of diseases experienced by this patient included alopecia totalis, vitiligo, psoriasis, Graves’ disease, CU, an autoimmune form of Lambert- Eaton myasthenic syndrome, and IgA deficiency. This patient had HLA genes that are found within the extended haplotype 8.1 AH (ancestral haplotype), which has been associated with the development of many autoimmune conditions.⁴⁵ These cases highlight that CU may occur as part of a larger constellation of autoimmune diseases in affected patients.

Therapeutic Interventions

Guidelines for the treatment of CU have been established using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system.^46,47 Second generation nonsedating H1 antihistamines are the first-line treatment for patients with CU.^48,49 If the patient fails first-line therapy after 2 weeks, secondline therapy involves increasing the dose of antihistamines used, up to four times the standard dose.⁵⁰ Patients should be advised that symptoms of sedation and drug interactions may occur with the increased dose of antihistamines. Cetirizine, desloratadine, fexofenadine, and bilastine (the latter is not licensed for use in Canada) were determined to be the safest antihistamines to up dose.⁵¹ In an estimated 50% of patients, symptoms persist following the use of antihistamines alone.^52,53 Third-line treatment involves changing the antihistamine used or adding a leukotriene antagonist. Leukotriene antagonists have been shown to improve patients with ASA or NSAID intolerant CU, ASST positive CU, and food-additive hypersensitivity induced CU, but not chronic idiopathic urticaria.⁵⁴ A short 3 to 7 day course of systemic steroids may be used in conjunction with the thirdline treatment options.⁵⁵ If third-line therapy fails, fourth-line therapeutic options include adding cyclosporine A, H2 blockers, dapsone or omalizumab.⁵⁶

The most effective fourth-line treatment in CU is thought to be omalizumab,⁵⁶ a humanized monoclonal antibody against IgE, approved for treatment of severe asthma. Maurer et al. published a randomized, double-blind study assessing the efficacy of omalizumab in patients with CU that had failed first-line treatment and found it significantly reduced CU symptoms.⁵⁷ Omalizumab reduces free IgE and the levels of the high affinity IgE receptor present on mast cells and basophils,⁵⁸ thereby resulting in decreased activation of mast cells and basophils, the cells hypothesized to be responsible for the development of hives in CU.

Additional treatment options reported in the literature for patients that fail fourth-line treatment include mycophenolate mofetil,⁵⁹ hydroxychloroquine,⁶⁰ methotrexate,⁶¹ tacrolimus,⁶² sulfasalazine⁶³ and intravenous immunoglobulin (IVIG)⁶⁴.

Treatment of concomitant thyroid disease was reported to induce remission of CU.⁶⁵ Kirkpatrick performed a study on CU patients with evidence of clinical or serological thyroid autoimmunity.⁶⁶ These patients had previously failed firstline treatment with antihistamines. It was demonstrated that in patients with thyroid autoimmunity and CU levothyroxine induced remission of angioedema and urticaria in all six subjects. Rumbryt reported that seven out of ten euthyroid patients with anti-thyroid antibodies experienced clinical remission of CU following treatment with thyroxine, but relapsed once therapy was stopped.⁶⁷ These studies suggest that in patients with CU the clinical identification and management of thyroid autoimmunity with levothyroxine may play a role in inducing remission of CU. However, Magen et al. recently reviewed patients with CU and thyroid disease treated with levothyroxine and compared them to untreated euthyroid controls.⁶⁸ The patients treated with levothyroxine experienced a clinical improvement in urticaria; however, the same improvement in symptoms was also noted in the euthyroid controls. This led to the conclusion that improvement of clinical symptoms in CU occurred spontaneously, independent of thyroid treatment. The conflicting literature regarding the impact of treatment of thyroid autoimmunity on the clinical course of CU indicates the need for larger studies to establish the role of levothyroxine in patients with CU.

NSAID use has been shown to aggravate CU symptoms in approximately 20% of patients with a prior CU diagnosis.⁶⁹ NSAIDs are commonly used to manage the pain and inflammation associated with RA, inflammatory spondyloarthropathies, and lupus arthritis. Autoimmune inflammatory arthropathies, especially RA, have been shown to occur more frequently in patients with CU than the general population.²¹ Therefore, exacerbation of symptoms due to NSAID use should be monitored in patients with CU and autoimmune inflammatory arthropathies. Zembowicz et al. demonstrated that selective COX-2 inhibitors do not induce urticaria in patients with CU that is aggravated by NSAIDs.⁷⁰ This suggests that selective COX-2 inhibitors may be preferred over general NSAIDs to prevent exacerbation of CU symptoms.

Helicobacter pylori (H. pylori) infection has been previously hypothesized to be an etiological factor in CU. This was based on reports demonstrating a high prevalence of H. pylori infection amongst CU patients,⁷¹ and improvement of clinical symptoms following H. pylori eradication^72,73. However, this hypothesis was brought into question by the fact that other authors have found no difference in the prevalence of H. pylori between those with CU and controls,⁷⁴ and no difference in autoantibody production,²⁴ as well as the additional finding that H. pylori eradication did not affect clinical outcomes⁷⁵. This divergence in the literature has been speculated to occur because of different detection methods, resistance to therapy, and the possibility of recurrences of H. pylori shortly after therapy.⁷⁶ To further complicate the issue, recent evidence suggests that H. pylori eradication may trigger CU.⁷⁷ Shakouri et al. completed a review of the literature regarding H. pylori eradication and CU using the GRADE system, and concluded that the evidence for treatment was weak and larger studies are needed to establish if H. pylori eradication is beneficial to CU patients.⁷⁸

Conclusion

CU is defined as hives lasting longer than 6 weeks. Currently, it is thought that up to 50% of CU is caused by autoimmune mechanisms.¹⁴ Autoantibodies to the high affinity IgE receptor are the most commonly identified offender, activating mast cells, basophils, and the complement system, resulting in the wheal and flare reaction.^14,16 CU is hypothesized to occur because of a predisposition in the patient to develop autoimmune diseases. In concordance with this hypothesis, additional autoimmune diseases are observed in patients with CU. Thyroid disease, particularly hypothyroidism, is the most common additional autoimmune disease diagnosed.²¹ Furthermore, thyroid disease may directly exacerbate CU severity by activating the complement system.^30,31 Other autoimmune diseases that occur more frequently in patients with CU include RA, SLE, vitiligo, pernicious anemia, celiac disease, and Sjörgen’s syndrome.^21,36 In case reports, CU has been identified as part of a larger autoimmune phenotype.^19,45 These associations support the theory that patients who develop CU do so because of an innate propensity to mount autoimmune reactions. Treatment of thyroid disease has been reported in the literature to have varying effects on CU, as it has been demonstrated to induce remission^65-67 and alternatively to have no effect on the clinical symptoms of CU⁶⁸. Autoimmune diseases occurring in patients with CU, especially thyroid disease, may be an important therapeutic target, but further studies are needed to establish the role of treatment on the clinical course of CU.

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